Figures & data
Figure 1. Tumor vessels are structurally and functionally abnormal.
Endothelial cells lining tumor vessels demonstrate aberrations in shape, they are hyperproliferative and hypermigrative and are often separated by wide and irregular inter-endothelial junctions. In addition, tumor vessels are covered by fewer pericytes, which are often detached from endothelial cells. These structural abnormalities lead to hypoperfusion and hypoxia, which stimulate cancer cells to escape and metastasize in distant organs. Moreover, the accompanying functional aberrations limit delivery and distribution of chemotherapeutics to and into the tumors. BM: basement membrane. Adapted from [Citation9].
![Figure 1. Tumor vessels are structurally and functionally abnormal.Endothelial cells lining tumor vessels demonstrate aberrations in shape, they are hyperproliferative and hypermigrative and are often separated by wide and irregular inter-endothelial junctions. In addition, tumor vessels are covered by fewer pericytes, which are often detached from endothelial cells. These structural abnormalities lead to hypoperfusion and hypoxia, which stimulate cancer cells to escape and metastasize in distant organs. Moreover, the accompanying functional aberrations limit delivery and distribution of chemotherapeutics to and into the tumors. BM: basement membrane. Adapted from [Citation9].](/cms/asset/70b68fa7-4f62-47de-a064-5479e9cc2c0c/iett_a_1282465_f0001_oc.jpg)
Table 1. Clinical studies investigating vascular normalization in humans.
Figure 2. Targeting endothelial cell metabolism induces tumor vessel normalization.
a. Schematic representation of the glycolytic pathway converting glucose into pyruvate. PFKFB3 is a key regulator of glycolysis by producing fructose-2,6-bisphosphate (F2,6P2), the most potent allosteric activator of phosphofructokinase-1 (PFK-1). G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F2,6P2, fructose-2,6-bisphosphate; PFK, phospho-fructokinase; 3PG, 3-phospho glyceraldehyde; TCA, tricarboxylic acid cycle; ATP, cellular adenosine 5ʹ-trisphosphate.
b. Upon inhibition of PFKFB3 in hyperglycolytic tumor endothelial cells, tumor vessels show smoother endothelial surface, reduced intercellular gaps, more prominent basement membrane and increased pericyte coverage. All these changes improve tumor vessel perfusion and thereby lower hypoxia, contributing to reduced invasion, intravasation and metastasis. Adapted from [Citation8].
![Figure 2. Targeting endothelial cell metabolism induces tumor vessel normalization. a. Schematic representation of the glycolytic pathway converting glucose into pyruvate. PFKFB3 is a key regulator of glycolysis by producing fructose-2,6-bisphosphate (F2,6P2), the most potent allosteric activator of phosphofructokinase-1 (PFK-1). G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F2,6P2, fructose-2,6-bisphosphate; PFK, phospho-fructokinase; 3PG, 3-phospho glyceraldehyde; TCA, tricarboxylic acid cycle; ATP, cellular adenosine 5ʹ-trisphosphate.b. Upon inhibition of PFKFB3 in hyperglycolytic tumor endothelial cells, tumor vessels show smoother endothelial surface, reduced intercellular gaps, more prominent basement membrane and increased pericyte coverage. All these changes improve tumor vessel perfusion and thereby lower hypoxia, contributing to reduced invasion, intravasation and metastasis. Adapted from [Citation8].](/cms/asset/d626d55c-b0e1-4d2d-bd32-2151e4efba07/iett_a_1282465_f0002_oc.jpg)
